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Antibiotics and intestinalprobiotics

intestinal dysbiosis: a place forprobiotics?

Hans Hoekstra, M.D., Ph.D.

Jheronimus Bosch Teaching HospitalJheronimus Bosch Teaching Hospital

‘s-Hertogenbosch, The Netherlands

Disclosures

Biocodex

- Speaker

- Support of the Asia Pacific Probiotics

Abbott

- Speaker

Disclosures

Probiotics Committee

Antibiotics are the Most Commonly used

Drugs in Western Countries

Antibiotics are the Most Commonly used

Drugs in Western Countries

Global Consumption

TP Van Boeckel, Lancet Infect Dis.2014 742–750,

Consumption of Antibiotics

Global Consumption

TP Van Boeckel, Lancet Infect Dis.2014 742–750

Consumption of Antibiotics

Use of antibiotics age in low resource settingsUse of antibiotics age in low resource settings

First antibiotic use

age <2 years

Rogawski ET et al. Bull World Health Organ 2017;95:49-61

Antibiotic prescription (age groups; 1000 individuals)

Antibiotic prescription (age groups; 1000 individuals)

Antibiotic consumption in lifestockAntibiotic consumption in lifestock

The ‘miracle’

• Discovery of penicillin

revolutionised treatment of

infectious diseaseinfectious disease

• Increased life expectancy

ability to prevent and treat

infection

‘miracle’ of antibiotics

penicillin

revolutionised treatment of

1. Armstrong GL et al, JAMA 1999;281(1):61

Increased life expectancy due to

prevent and treat

The ‘miracle’ ‘miracle’ of antibiotics


Crude mortality rates for

all causes, non infectious

causes and infectious

diseases over the period

1900-1996.

The ‘miracle’

NOTE

Already Already

falling

before

antibioti

c era

‘miracle’ of antibiotics


Crude mortality rates for

all causes, non infectious

causes and infectious

diseases over the period

1900-1996.

Consequences of Antibiotic (

• Antibiotic resistance

• Disruption to microbiome

• Adverse drug events

• Drug side effects

• Clostridium difficile infection

• Antibiotic associated diarrhea/colitis

• Increased hospital readmissions

• Increased health-care costs

Consequences of Antibiotic (Mis)use

infection

Antibiotic associated diarrhea/colitis

Increased hospital readmissions

Ohl CA, Luther VP. J. Hosp. Med. 2011;6:S4

No significant new antibiotic discoveries for 30 years!No significant new antibiotic discoveries for 30 years!

Antibiotic use and antibiotic

Relationship between total antibiotic consumption and

pneumoniae resistance to penicillin in 20 industrialised countries

18. Shaban RZ, Cruickshank M, Christiansen K & the Antimicrobial Resistance Standing Committee (2013), p. 6.

National Surveillance and Reporting of Antimicrobial Resistance and Antibiotic Usage for Human Health in Australia.

Antimicrobial Resistance Standing Committee, Australian Heath Protection Principal Committee: Canberra.

Antibiotic use and antibiotic resistance

Relationship between total antibiotic consumption and Streptococcus

resistance to penicillin in 20 industrialised countries

18. Shaban RZ, Cruickshank M, Christiansen K & the Antimicrobial Resistance Standing Committee (2013), p. 6.

National Surveillance and Reporting of Antimicrobial Resistance and Antibiotic Usage for Human Health in Australia.

Antimicrobial Resistance Standing Committee, Australian Heath Protection Principal Committee: Canberra.

Emergence of antibiotic

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing

them to concentrations not sufficient to kill them, and the same thing has occasionally

happened in the body.”

Sir Alexander Fleming, 1945

of antibiotic resistance

4. Sir Alexander Fleming, Nobel Lecture, December 1945

5. Pray LA Insight Pharma Reports 2008, in Looke D ‘The Real Threat of Antibiotic Resistance’

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing

them to concentrations not sufficient to kill them, and the same thing has occasionally

Resistance spreadsspreads rapidly

Natural selection

6. Centers for Disease Control and Prevention http://www.cdc.gov/hai/

Natural selection

Horizontal transfer

International travel

“The magnitude of the problem is now accepted.

We estimate that by 2050, 10 million lives a year and

a cumulative 100 trillion USD of economic output are

at risk due to the rise of drug resistant infections if

we do not find proactive solutions now to slow down

the rise of drug resistance.

Even today, 700,000 people die of resistant infections

every year.”

https://amr-review.org/home.html

Closed 2016

“The magnitude of the problem is now accepted.

We estimate that by 2050, 10 million lives a year and

a cumulative 100 trillion USD of economic output are

at risk due to the rise of drug resistant infections if

we do not find proactive solutions now to slow down

Even today, 700,000 people die of resistant infections

www. weforum.org consulted on February 2 2017

Antimicrobial stewardship

Antimicrobial stewardship refers to coordinated interventions designed to improve and measure the appropriate use of antimicrobials by promoting the selection antimicrobial drug regimen, dose, duration of therapy, and route of administration.of administration.

Antimicrobial stewards seek to achieve optimal clinical outcomes related to antimicrobial use, minimize toxicity and other adverse events, reduce the costs of health care for infections, selection for antimicrobial resistant strains.

Antimicrobial stewardship

coordinated interventions designed to improve and measure the appropriate use of

promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route

Antimicrobial stewards seek to achieve optimal clinical outcomes related to antimicrobial use, minimize toxicity and other adverse events, reduce the costs of health care for infections, and limit the selection for antimicrobial resistant strains.

Long-term probiotic (LGG) consumption reduces antibiotic useterm probiotic (LGG) consumption reduces antibiotic use

DB PC RCT

(231 children, aged 2-7 yrs)

Duration: 210 days

Korpela K, et al. PlosOne: April 25, 2016

: 400 ml milk with LGG 108 cfu/ml

: 400 ml milk

After antibiotic exposure

Antibiotic

Normal HGMDisruption HGM due to

antibiotic exposure

Bouhnik Y. Gut Microflora Digestive Physiology And Pathology. Paris; 2009:181-197.

Disruption Microbiome

After antibiotic exposure

Short Chain

Fatty Acids

Luminal

Osmosis

Tight

Junctions Disruption

Disturbed HGM and infection

(e.g., C difficile)

Inflammation

AADDisruption Microbiome

Disruption to microbiome (dysbiosis)

• Numbers

• Balance• Balance

• Diversity

Disruption to microbiome (dysbiosis)

Counterintuitive results

An increase of bacterial load after ATB intake in fecal sample, …

1,5E+11

2E+11

2,5E+11

3E+11

3,5E+11

4E+11

co

py n

um

ber

of

16S

rR

NA

gen

e p

er

g o

f fe

ces

*

P = 0.08 (Wilcoxon matched-pairs signed rank test)

0

5E+10

1E+11

1,5E+11

BF_ATB AF_ATB

co

py n

um

ber

of

16S

rR

NA

gen

e p

er

g o

f fe

ces

Day 0 Day 7

Counterintuitive results

An increase of bacterial load after ATB intake in fecal sample, …

pairs signed rank test)

Panda et al, PLoS ONE 2014

Day 7

… and a … and a shiftshift in balance at in balance at in balance at in balance at philumphilum levellevel


….., but a decrease on bacterial richness (taxa)….., but a decrease on bacterial richness (taxa)

Average number of observed taxa before antibiotic intake:

Average number of observed taxa after antibiotic intake: 105 (SD = 23)

p < 0.0001 (Wilcoxon matched-pairs signed rank test) for observed species and chao1

p < 0.0001 (Paired t test)

….., but a decrease on bacterial richness (taxa)….., but a decrease on bacterial richness (taxa)

antibiotic intake: 140 (SD = 22)

antibiotic intake: 105 (SD = 23)

pairs signed rank test) for observed species and chao1


C: no AB past 2 yrs and in total <1 course/yr

E: AB in early life + C

M6: macrolide course within last 6 mo

M12: macrolide course within 6-12 mo

M24: macrolide course within 12-24 mo

P6, P12, P24: penicillin courses ….

Disturbances of the gut microbiota & dysbiosis Disturbances of the gut microbiota &

EUBIOSIS => “Normal" and "balanced"

intestinal microbiota fulfills all the

conditions for us to benefit from its

health effects

(metabolism, immunity, trophicity, barrier

effect)

vs

Moré, Margret I., Alexander Swidsinski. "Saccharomyces boulardii CNCM I-745 supports regeneration

the intestinal microbiota after diarrheic dysbiosis–a reviewClinical and Experimental Gastroenterology

11 (2015): 237

DYSBIOSIS => Intestinal dysbiosis can

be defined as an unfavorable

dysbalance of the intestinal

microbiota.

vs

The course of life of a The course of life of a microbiota

Antibiotics and the microbiome throughout developmentAntibiotics and the microbiome throughout development

Langdon et al Genome Med 2016, 8:39, 260

Disorders linked to altered composition of the gut microbiota:

Nutrition-related disorders (obesity, type 2 diabetes and the metabolic syndrome)

Inflammatory bowel diseases (UC and CD)

Celiac disease

Antibiotic-associated diarrhea, recurrent diarrhea by C. difficileAntibiotic-associated diarrhea, recurrent diarrhea by C. difficile

Functional bowel disorders

Colo-rectal cancer

Certain allergies

Certain mental and neuro-developmental conditions, such as autism spectrum disorders

Disorders linked to altered composition of the gut microbiota:

related disorders (obesity, type 2 diabetes and the metabolic syndrome)

associated diarrhea, recurrent diarrhea by C. difficileassociated diarrhea, recurrent diarrhea by C. difficile

developmental conditions, such as autism spectrum disorders

Associations, but no proven causuality

, but no proven

Consequences of Antibiotic (

• Antibiotic resistance

• Disruption to microbiome

• Adverse drug events

• Drug side effects

• Antibiotic associated diarrhea/colitis

• Clostridium difficile infection

• Increased hospital readmissions

• Increased health-care costs

Consequences of Antibiotic (Mis)use

Antibiotic associated diarrhea/colitis

infection

Increased hospital readmissions

Ohl CA, Luther VP. J. Hosp. Med. 2011;6:S4

Definition of antibiotic-associated diarrhea (AAD)

Diarrhea associated with antibiotic exposure either while on antibiotics and up to 8 weeks after the end of therapy

Definition of CDAD: AAD + presence of

associated diarrhea (AAD)

exposure either while on antibiotics and up to 8 weeks after the end of therapy

of Clostridium difficile in the stools

• Incidence in children: ~ 20-25% (ranges 6

• Peak age 18-48 months

• Clostridium difficile is the major agent of AAD (25

Antibiotic-associated diarrhea in children

• Mostly mild-moderate severity, abdominal

• Is more severe in chronic diseases: GI and previous episode of AAD

• Prevention: antibiotic stewardship, probiotics

25% (ranges 6-80%)

major agent of AAD (25-30% of cases)

associated diarrhea in children

abdominal pain (35%)

: GI pathology, immunosuppression

, enhanced infection control,

• Large spectrum antibiotics

• Antibiotics with high biliary excretion

• Prolonged antibiotic therapy

Antibiotic therapy with increased risks

• Prolonged antibiotic therapy

• Repeated antibiotics cycles

• Antibiotic combination therapies

Antibiotics with high biliary excretion

Antibiotic therapy with increased risks

macrolidemacrolidemacrolidemacrolide

fluoquinolonesfluoquinolonesfluoquinolonesfluoquinolones

tetracyclinestetracyclinestetracyclinestetracyclines

ampicillinampicillinampicillinampicillin

5

5

5

10

Major c Classes of antibiotics responsable for diarrhea of antibiotics responsible for diarrhea

0 10

amoxiamoxiamoxiamoxi----clavulanateclavulanateclavulanateclavulanate

clindamycinclindamycinclindamycinclindamycin

gen cephalosporinsgen cephalosporinsgen cephalosporinsgen cephalosporins

%

Classes of antibiotics responsable for diarrhea lasses

of antibiotics responsible for diarrhea

20 30 40

20

25

30

%

CD -Associated

Diarrhea

CD

colitis

Pseudomembranous

Spectrum of Clostridium difficile

Asymptomatic

Carrier

Diarrhea

(CDAD/CDI)

colitis

Risk factors

colitis

Pseudomembranous

colitis

Fulminant colitis

Toxic megacolon

Clostridium difficile infections difficile infection

colitis

• Essential: Discontinuation or changing the type of the inciting antibiotic and giving oral rehydration therapy

• Probiotics?

Therapy for AAD and CDAD

• Probiotics?

Essential: Discontinuation or changing the type of the inciting antibiotic and giving oral rehydration therapy

Therapy for AAD and CDAD

Goldenberg JZ, LytvynL, Steurich J, Parkin P, Mahant S, Johnston BC

LGG

Clearly, current evidence favors the use of probiotics in the

prevention of symptoms of AAD. Lactobacilli, S. boulardii, and

selected multistrain combinations, in appropriate dosages, are

clinically useful. The safety profile, with the exceptions noted

earlier, is acceptable particulary in view of the shortL.Acidophilu

s

Saccharomyce

s boulardii

earlier, is acceptable particulary in view of the short

an antibiotic when accompanied by a probiotic.

Clearly, current evidence favors the use of probiotics in the

prevention of symptoms of AAD. Lactobacilli, S. boulardii, and

selected multistrain combinations, in appropriate dosages, are

clinically useful. The safety profile, with the exceptions noted

earlier, is acceptable particulary in view of the short-term use of earlier, is acceptable particulary in view of the short-term use of

an antibiotic when accompanied by a probiotic.

Recommendations for AntibioticAntibiotic-Associated Diarrhea

ESPGHAN recommendations according to the GRADE

system

Strong recommendation (SR): when the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not

Weak recommendation (WR): when the trade

Recommendations are formulated if

Disclaimer:

- recommendations may be modified in a specific country habits, availability, quality and costs

- recommendations were for Europe (well-nourished

ESPGHAN recommendations according to the GRADE

hen the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not

hen the trade-offs are less certain

at least 2 RCTs are available

country based on health care organisation, local

nourished children)

Methodological limits in RCTS on prevention of AAD with probiotics

Methodological limits in RCTS on prevention of AAD with probiotics

Szajewska et al JPGN March 2016

LGG for prevention

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42:1149

5 RCTs, n=445

Risk Ratio: 0.48

(0.26 to 0.89)

NNT=8

prevention pediatric AAD

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42:1149-

SB for prevention

6 RCTs, n=1653

Risk Ratio: 0.43

(0.60 to 0.30)

NNT=9

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42: 793

NNT=9

prevention pediatric AAD

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42: 793-801

PROBIOTIC STRAIN STUDIES IN

SUPPORT

QUALITY OF

EVIDENCE

5 RCTs Moderate

S. boulardii CNCM I-6 RCTs Moderate

Recommended strains by ESPGHAN Working Group for AAD

S. boulardii CNCM I-6 RCTs Moderate

GRADE OF

RECOMMENDATIONRECOMMENDATION

Strong May be considered


Recommended strains by ESPGHAN Working Group for AAD


PROBIOTIC STRAIN STUDIES IN

SUPPORT

B. clausii 1 RCT

L. acidophilus

L. bulgaricus1 RCT

L. acidophilus

B. infantis1 RCT

L. acidophilus

B. breve1 RCT

L. Acidophilus, L. rhamnosus

L. bulgaricus, L. casei

Other strains used in AAD

L. bulgaricus, L. casei

Str. thermophilus

B. infantis, B. breve

1 RCT

L. rhamnosus E/N, Oxy, Pen 1 RCT

L. Rhamnosus GG

Bb-12

L. Acidophilus La-5

1 RCT

B. longum PL03

L. rhamnosus KL53A

L. plantarum PL02

1 RCT

B. lactis B12

Str. termophilus1 RCT

Kefir 1 RCT

RECOMMENDATION

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Insufficient data

Recommendations: Recommendations:

If the use of probiotics for preventing AAD

existence of risk factors such as class of antibiotic(s), duration of

antibiotic treatment, age, hospitalization, comorbidities, or previous

episodes of AAD, the WG recommends using

GG and Sacharomyces boulardii (both: Strong Recommendation)

preventing AAD is considered because of the

existence of risk factors such as class of antibiotic(s), duration of

antibiotic treatment, age, hospitalization, comorbidities, or previous

episodes of AAD, the WG recommends using Lactobacillus rhamnosus

(both: Strong Recommendation)

SB for prevention

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42: 793

2 RCTs, n=579

Risk Ratio: 0.25

(0.08 to 0.73)

prevention pediatric CDAD

H. Szajewska et al. Aliment Pharmacol Ther 2015; 42: 793-801

Recommendations: Recommendations:

If the use of probiotics for preventing CDAD is considered, the WG

recommends using Sacharomyces boulardii

If the use of probiotics for preventing CDAD is considered, the WG

Sacharomyces boulardii (Weak Recommendation)

What could probiotic use mean in practice?

- 50-60% risk reduction of AAD =

=

=

=

=

=

=

� Cost

� Recovery

What could probiotic use mean in practice?

= � risk of interruption of antibiotic

= � change of antibiotic treatment

= � risk of resistance to antibiotics

= � side effects

= � cost (e.g., duration of hospitalization}

= � compliance to antibiotics

= � recovery

Cost

Recovery

Recommendations in other continentsRecommendations in other continents

Europe USA Latin America

Acute

gastroenteritis

T L. rhamnosus GG,

S. boulardii,

L reuteri

L. rhamnosus GG,

S. boulardii

L. rhamnosus

S. boulardii

L. reuteri

Recommendations for use of probiotics in childhood

intestinal diseases by geographic region

AAD P L. rhamnosus GG,

S. boulardii

L. rhamnosus GG,

S. boulardii

L. rhamnosus

S. boulardii

CDAD P S. boulardii

Latin America World APAC

(Cameron et al. 2017)c

rhamnosus GG,

boulardii,

reuteri

S. boulardii,

L. rhamnosus GG,

Indian Dahi

S. boulardii,

L. rhamnosus GG,

L reuteri

Recommendations for use of probiotics in childhood

diseases by geographic region

rhamnosus GG,

boulardii

S. boulardii;

L. rhamnosus GG,

B. lactis Bb12 + S.

thermophilus,

L. rhamnosus strains

E/N, Oxy and Pen

L rhamnosus GG

S.boulardii,

S. boulardii

Studies organized worldwide show:

Frequent misidentification and misclassification of strains

Contamination, sometimes with pathogens

No viable strains, false labelling of number of colonies

Probiotic products: A call for improved quality control

Deminishment of functional properties, shelf live






S. Kolaceck et al. A position paper by the ESPGHAN

Working Group for Probiotics and Prebiotics, JPGN

2017, in press














2017, in press







→ Health authori es should play their control role, in par cular

for the use in vulnerable populations, and for evidence in defined

clinical conditions as other pharmaceutical products






→ Health authori es should play their control role, in par cular

for the use in vulnerable populations, and for evidence in defined

clinical conditions as other pharmaceutical products



2017, in press

Antibiotic use in children could lead to long term disruption of the

microbiome with unknown, and possibly harmful, health effects

Safe medical therapies (probiotics) are available for AAD/CDAD

Positive evidence with probiotic drugs in these conditions mainly comes

Take home messages


from L. rhamnosus GG and S. boulardii

Many other probiotics strains cannot be recommended because of

insufficient data or insufficient data on quality

We need more good RCTs

Antibiotic use in children could lead to long term disruption of the

microbiome with unknown, and possibly harmful, health effects

Safe medical therapies (probiotics) are available for AAD/CDAD


Take home messages


S. boulardii CNCM I-745 strains

Many other probiotics strains cannot be recommended because of

insufficient data or insufficient data on quality

And now all thisdiscussion

this is open fordiscussion, �

Thank you!Thank you!

Probiotics and reduced spread of antibiotic resistance

Possible mechanisms:

• Better treatment of bacterial infection

• Concept of eubiosis vs dysbiosis

• Increased bacterial susceptibility to antibiotics?

• Prevention of spread of resistance factors?

• Antimicrobial compounds (e.g. SCFA, bacteriocin?) In vitro only

Probiotics and reduced spread of antibiotic resistance

Better treatment of bacterial infection

vs dysbiosis

Increased bacterial susceptibility to antibiotics?

Prevention of spread of resistance factors?

Antimicrobial compounds (e.g. SCFA, bacteriocin?) In

Ouwehand AC, et al. Ann Med 2016

Decrease % of HGM biodiversity across studies with different antibiotic exposures

Decrease % of HGM biodiversity across studies with different antibiotic exposures

Vangay, Pajau, et al. "Antibiotics, pediatric

dysbiosis, and disease." Cell host & microbe 17.5

(2015): 553-564.

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